Under most physiological conditions in animals and in man, the rate of cholesterol synthesis is limited by the rate of intracellular mevalonic acid (MVA) production. We and others have shown that MVA can be detected in plasma and urine in amounts proportional to the rate of whole body cholesterol production when patients are fed either solid food or MVA-free liquid formula diets. Moreover, plasma MVA levels show a pronounced diurnal rhythm in man that is suppressed by fasting or cholesterol feeding, suggesting diurnal changes in the rate of cholesterol synthesis. The simplest explanation of these observations is that a very small fraction of the intracellular MVA production leaks to the plasma compartment: less than 1 in 1000 molecules. It is not clear why MVA is lost from tissues to plasma or why the rate of MVA efflux from cells should reflect the ongoing rate of cholesterol synthesis. The fact that it does, however, offers the opportunity to develop a simple method for assessing changes in whole body cholesterol synthesis in man and laboratory animals. In contrast, currently accepted methods for measuring cholesterol synthesis (sterol balance and isotopic cholesterol kinetics) require a significant commitment of time and effort by patients and clinical investigators. The proposed research project is designed to gain a better understanding of the regulation of MVA metabolism. This will allow us to ascertain the feasibility of measuring whole body cholesterol synthesis in animal models and man by measurement of plasma MVA concentrations, daily output of MVA into the urine, or by analysis of turnover kinetics of plasma MVA. In the metabolic steady state whole body cholesterol synthesis will be measured by sterol balance techniques and compared to measurements of MVA production over a broad range of cholesterol synthetic rates in man. In rats and in non-human primates we will measure intracellular MVA production, efflux, turnover in the plasma compartment, and excretion into the urine, using labeled MVA. The project is designed to provide a better understanding of how plasma MVA concentrations are related to the rate of whole body cholesterol synthesis as the rationale for use of MVA as a simple and rapid approach in studies of the regulation of cholesterol synthesis in man.